According to the Centers for Disease Control and Prevention, cigarette smoking causes the vast majority of lung cancers and over 400,000 deaths annually with a total monetary cost exceeding $190 billion. While the majority of the 45+ million US smokers want to quit, a small fraction of this number actually succeeds. The most popular smoking cessation products utilize the nicotine replacement therapy (NRT) paradigm, but deliver cessation rates of less than 10%. Therefore, there is an urgent need for smoking cessation products that deliver higher efficacy than those currently marketed. With 7 million NRT users and over $800 million in annual US sales, the NRT market is well-established. Even though smokers experience peak cravings and smoke at predictable times throughout the day, existing NRT regimens are not tailored to systematically preempt these episodes. Therefore, there is a commercial opportunity for a programmable NRT (PNRT) product that leverages this important feature of smoking behavior to increase efficacy, with potential to save or prolong millions of lives and dramatically cut US healthcare costs. Chrono Therapeutics, Inc. (CTI) plans to produce a programmable wristwatch-like device, SmartStopTM, that delivers nicotine transdermally through a patch medium in pulses throughout the day. By tailoring the pulses to preempt the regular craving and peak smoking episodes that smokers experience,SmartStopTM is likely to significantly increase the efficacy of NRT. The end goal of this Fast-Track SBIR project is to produce a set of six prototypes of this device and to demonstrate their functionality in human pharmacokinetic (PK) trials. CTI will implement this project as follows: (i) Prototype the nicotine formulation dispensing unit by miniaturizing a pump and testing its performance. (ii) Demonstrate the ability of the dispensing unit to deliver nicotine through a skin sample. (iii) Produce six SmartStopTM prototypes for a clinical PK study that employs the pumping technology developed in (i) above. (iv) Demonstrate the capability of the prototypes to regulate plasma nicotine in human subjects using programmed pulses of nicotine formulation. SmartStopTM will be the only product that combines the time-tested principles of NRT with the latest science on the predictable nature of smoking. Therapeutic innovations include the ability to (i) automatically ensure compliance with a multi-dose regimen, (ii) customize for patient-specific levels of dependence and smoking patterns, (iii) administer nicotine automatically prior to waking to relieve peak morning craving without the side effects of night-long dosing, and (iv) decrease tolerance to nicotine by gradually tailoring-down the dose to wean the smoker off cigarettes. Technical innovations include (i) automated on-off for nicotine administration, (ii) miniaturization combined with full functionality and visual appeal, and (iii) key safety features including insulation of the nicotine reservoir from the skin and delivery and uptake mechanisms that limit risk of excessive dosage, which are absent from existing transdermal NRT products. PUBLIC HEALTH RELEVANCE: According to the Centers for Disease Control and Prevention, cigarette smoking causes the vast majority of lung cancers and over 400,000 deaths annually with a total monetary cost exceeding $190 billion. While the majority of the 45+ million US smokers want to quit, a small fraction of this number actually succeeds. Chrono Therapeutics, Inc. (CTI) plans to produce a programmable wristwatch-like device, SmartStopTM, that delivers tailored doses of nicotine through a patch in pulses throughout the day to preempt the regular craving and peak smoking episodes that smoker's experience, thereby significantly increasing the efficacy of nicotine replacement therapy and prolonging or saving millions of lives.